Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor tyrosine kinase superfamily, ALK fusion protein, mutation and overexpression thereof are associated with various diseases. ALK was firstly discovered in anaplastic large cell lymphoma (ALCL) cell lines, the fusion protein gene formed by translocation of the 2nd and the 5th balanced chromosomal contains the 3′ end portion of the ALK gene (including intracellular domain and protein kinase domain) and the nucleolar phosphoprotein gene (Nucleophosmin, NPM gene). Over twenty types of ALK fusion proteins produced by different chromosome rearrangements have been discovered. They participate in the pathogenesis of diseases including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, etc. EML4-ALK fusion protein and other four ALK fusion proteins play a fundamental role in the development of about 5% of non-small cell lung cancer. The downstream signaling pathways involving ALK fusion proteins involves Ras/Raf/MEK/ERK1/2 proliferation module and JAK/STAT cell survival pathway, and this intricate signal transduction network affects cell proliferation, differentiation and apoptosis. ALK kinase inhibitor can be used to treat cancer, autoimmune diseases and the like. In August 2011, Pfizer's selective ALK and c-Met dual inhibitor crizotinib (trade name Xalkori) was approved by the US Food and Drug Administration for the treatment of advanced lung small cell lung cancer. Drug-resistance emerges during the clinical application of Crizotinibs, thereby stimulating the development of second-generation ALK kinase inhibitor drugs, for the treatment of non-small cell lung cancer and other diseases.
Diaminopyrimidine compounds and derivatives thereof are a class of inhibitors for protein kinases such as ALK kinase. A series of diaminopyrimidine derivatives having 2,4-dual-substitutients on pyrimidine ring has been disclosed in WO2008073687 and WO2012106540. Wherein the compound LDK378 (CERITINIB), of which the chemical name is 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine, is a selective ALK kinase inhibitor, and it can be used in the treatment of cancer and cell proliferative diseases and other related diseases. At present, the compound is in the Phase II clinical trials of treating cell proliferative diseases (such as non-small cell lung cancer).
Although the targeted inhibition of different protein kinases is beneficial for the treatment of various kinase-related diseases, the discovery of novel compounds which specifically inhibit some protein kinase and has good druggability such as oral bioavailability is still very challenging. In addition, there are some side effects and drug resistance problems forh some currently available protein kinase inhibitors.
Thus, there is still a need in the art to develop compounds having kinases (e.g., ALK kinases) inhibitory activity or better pharmacodynamic/pharmacokinetics properties.